Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and in 2013 accounted for 1.5 million deaths. Fluoroquinolone antibacterials, which target DNA gyrase, are critical agents used to halt the progression from multidrug-resistant tuberculosis to extensively resistant disease; however, fluoroquinolone resistance is emerging and new ways to bypass resistance are required. To better explain known differences in fluoroquinolone action, the crystal structures of the WT Mtb DNA gyrase cleavage core and a fluoroquinolone-sensitized mutant were determined in complex with DNA and five fluoroquinolones. The structures, ranging from 2.4- to 2.6-Å resolution, show that the intrinsically low susceptibility of Mtb to fluoroquinolones correlates with a reduction in contacts to the water shell of an associated magnesium ion, which bridges fluoroquinolone–gyrase interactions. Surprisingly, the structural data revealed few differences in fluoroquinolone–enzyme contacts from drugs that have very different activities against Mtb. By contrast, a stability assay using purified components showed a clear relationship between ternary complex reversibility and inhibitory activities reported with cultured cells. Collectively, our data indicate that the stability of fluoroquinolone/DNA interactions is a major determinant of fluoroquinolone activity and that moieties that have been appended to the C7 position of different quinolone scaffolds do not take advantage of specific contacts that might be made with the enzyme. These concepts point to new approaches for developing quinolone-class compounds that have increased potency against Mtb and the ability to overcome resistance

A Political Economy of Privatization Contracts : The Case of Water and Sanitation in Ghana and Argentina

This document is the Accepted Manuscript version of the following article: Hulya Dagdeviren, Simon A. Robertson, 'A Political Economy of Privatization Contracts: The Case of Water and Sanitation in Ghana and Argentina', Competition & Change, Vol. 18 (2): 150-163, April 2014. The final, published version is available online at DOI: https://doi.org/10.1179/1024529414Z.00000000053. Published by SAGE.In general, the process and outcomes of privatization have been studied from the point of view of efficiency. In this article, we consider issues in the course of contract design, implementation, management and enforcement in privatized public services and utilities. The study is based on two case studies, involving several water concessions in Argentina and a management contract in the urban water sector in Ghana. Three key arguments are presented on the basis of these case studies. The first is that an individualistic analytical framework is often utilized by the mainstream economic perspectives, but these are inadequate for a comparative assessment of private versus public provision in public services where there are distinct collective or group interests and hence a wider socio-economic context and representation of different interests becomes highly important. Instead, the article proposes a political economy perspective, which pays due attention to distributional issues, group interests, ideology of states and power relations for the assessment of privatization contracts. Second, the administrative capacity of states and their resources play a key role for the outcomes of privatization. Finally, while some contractual issues could be resolved through resourcing and experience over time, others are inherent to the contractual relations with little prospect of remedy.Peer reviewe

Are Musical Autobiographical Memories Special? It Ain’t Necessarily So

We compared young adults’ autobiographical (AB) memories involving Music to memories concerning other specific categories and to Everyday AB memories with no specific cue. In all cases, participants reported both their most vivid memory and another AB memory from approximately the same time. We analyzed responses via quantitative ratings scales on aspects such as vividness and importance, as well as via qualitative thematic coding. In the initial phase, comparison of Music-related to Everyday memories suggested all Musical memories had high emotional and vividness characteristics whereas Everyday memories elicited emotion and other heightened responses only in the “vivid” instruction condition. However, when we added two other specific AB categories (Dining and Holidays) in phase two, the Music memories were no longer unique. We offer these results as a cautionary tale: before concluding that music is special in its relationship to cognition, perception, or emotion, studies should include appropriate control conditions

Superscaling analysis of the Coulomb Sum Rule in quasielastic electron-nucleus scattering

The Coulomb sum rule for inclusive quasielastic electron scattering in $^{12}$C, $^{40}$Ca and $^{56}$Fe is analyzed based on scaling and superscaling properties. Results obtained in the relativistic impulse approximation with various descriptions of the final state interactions are shown. A comparison with experimental data measured at Bates and Saclay is provided. The theoretical description based on strong scalar and vector terms present in the relativistic mean field, which has been shown to reproduce the experimental asymmetric superscaling function, leads to results that are in fair agreement with Bates data while it sizeably overestimates Saclay data. We find that the Coulomb sum rule for a momentum transfer $q\geq 500$ $MeV/c$ saturates to a value close to 0.9, being very similar for the three nuclear systems considered. This is in accordance with Bates data, which indicates that these show no significative quenching in the longitudinal response.Comment: 22 pages, 6 figures. To be published in Phys. Lett.

Trust and control interrelations: New perspectives on the trust control nexus

This article is the post-print version of the published article that may be accessed at the link below. Copyright @ 2007 Sage Publications.This article introduces the special issue on New Perspectives on the Trust-Control Nexus in Organizational Relations. Trust and control are interlinked processes commonly seen as key to reach effectiveness in inter- and intraorganizational relations. The relation between trust and control is, however, a complex one, and research into this relation has given rise to various and contradictory interpretations of how trust and control relate. A well-known discussion is directed at whether trust and control are better conceived as substitutes, or as complementary mechanisms of governance. The articles in this special issue bring the discussion on the relationship between both concepts a step further by identifying common factors, distinctive mechanisms, and key implications relevant for theory building and empirical research. By studying trust and control through different perspectives and at different levels of analysis, the articles provide new theoretical insights and empirical evidence on the foundations of the trust-control interrelations

High Folate, Perturbed One-Carbon Metabolism and Gestational Diabetes Mellitus

Folate is a dietary micronutrient essential to one-carbon metabolism. The World Health Organisation recommends folic acid (FA) supplementation pre-conception and in early pregnancy to reduce the risk of fetal neural tube defects (NTDs). Subsequently, many countries (~92) have mandatory FA fortification policies, as well as recommendations for periconceptional FA supplementation. Mandatory fortification initiatives have been largely successful in reducing the incidence of NTDs. However, humans have limited capacity to incorporate FA into the one-carbon metabolic pathway, resulting in the increasingly ubiquitous presence of circulating unmetabolised folic acid (uFA). Excess FA intake has emerged as a risk factor in gestational diabetes mellitus (GDM). Several other one-carbon metabolism components (vitamin B12, homocysteine and choline-derived betaine) are also closely entwined with GDM risk, suggesting a role for one-carbon metabolism in GDM pathogenesis. There is growing evidence from in vitro and animal studies suggesting a role for excess FA in dysregulation of one-carbon metabolism. Specifically, high levels of FA reduce methylenetetrahydrofolate reductase (MTHFR) activity, dysregulate the balance of thymidylate synthase (TS) and methionine synthase (MTR) activity, and elevate homocysteine. High homocysteine is associated with increased oxidative stress and trophoblast apoptosis and reduced human chorionic gonadotrophin (hCG) secretion and pancreatic β-cell function. While the relationship between high FA, perturbed one-carbon metabolism and GDM pathogenesis is not yet fully understood, here we summarise the current state of knowledge. Given rising rates of GDM, now estimated to be 14% globally, and widespread FA food fortification, further research is urgently needed to elucidate the mechanisms which underpin GDM pathogenesis.Jessica M. Williamson, Anya L. Arthurs, Melanie D. Smith, Claire T. Roberts, and Tanja Jankovic-Karasoulo

Tight-binding study of the influence of the strain on the electronic properties of InAs/GaAs quantum dots

We present an atomistic investigation of the influence of strain on the electronic properties of quantum dots (QD's) within the empirical $s p^{3} s^{*}$ tight-binding (ETB) model with interactions up to 2nd nearest neighbors and spin-orbit coupling. Results for the model system of capped pyramid-shaped InAs QD's in GaAs, with supercells containing $10^{5}$ atoms are presented and compared with previous empirical pseudopotential results. The good agreement shows that ETB is a reliable alternative for an atomistic treatment. The strain is incorporated through the atomistic valence force field model. The ETB treatment allows for the effects of bond length and bond angle deviations from the ideal InAs and GaAs zincblende structure to be selectively removed from the electronic-structure calculation, giving quantitative information on the importance of strain effects on the bound state energies and on the physical origin of the spatial elongation of the wave functions. Effects of dot-dot coupling have also been examined to determine the relative weight of both strain field and wave function overlap.Comment: 22 pages, 7 figures, submitted to Phys. Rev. B (in press) In the latest version, added Figs. 3 and 4, modified Fig. 5, Tables I and II,.and added new reference

Predictors of combined cognitive and physical decline

OBJECTIVES: To determine the incidence and correlates of combined declines in cognitive and physical performance. DESIGN: Cohort study of community-dwelling older women with moderate to severe disability. SETTING: The community surrounding Baltimore, Maryland. PARTICIPANTS: Participants in the Women's Health and Aging Study I with Mini-Mental State Examination (MMSE) score or 24 or greater and walking speed greater than 0.4 m/s at baseline. MEASUREMENTS: Cognitive decline was defined as an MMSE score less than 24 and physical decline as a walking speed of 0.4 m/s or less in at least one of the three annual follow-up visits. Participants were stratified into groups based on cognitive or physical decline or both. Group characteristics were compared, and results were adjusted for age, race, education, and significant covariates. RESULTS: Of 558 women that met the baseline MMSE and walking speed inclusion criteria, 21% developed physical decline, 12% developed cognitive decline, and 11% experienced combined cognitive and physical decline. After adjustment, physical decline was associated with age, nonwhite race, former smoking, baseline walking speed, and instrumental activities of daily living (IADL) impairment. Cognitive decline was associated with age and baseline MMSE score. Combined decline was associated with age, baseline walking speed, MMSE score, IADL impairment, as well as current smoking (odds ratio (OR)=5.66, 95% confidence interval (CI)=1.49-21.54) and hemoglobin level (OR=0.68, 95% CI=0.47-0.98). CONCLUSION: Potential predictors of cognitive and physical performance decline were identified. The association between smoking and lower hemoglobin levels and combined cognitive and physical decline may represent potentially modifiable risk factors and should be confirmed in future studie

The influence of anxiety on the progression of disability

OBJECTIVES: To determine the influence of anxiety on the progression of disability and examine possible mediators of the relationship. DESIGN: Community-based observational study. SETTING: Women's Health and Aging Study I, a prospective observational study with assessments every 6 months for 3 years. PARTICIPANTS: One thousand two functionally limited women aged 65 and older. MEASUREMENTS: Anxiety symptoms were assessed using four questions from the Hopkins Symptom Checklist (nervous or shaky, avoidance of certain things, tense or keyed up, fearful). Participants who reported experiencing two or more of these symptoms at baseline were considered anxious. Anxiety as a predictor of the onset of four types of disability was examined using Cox proportional hazards models. Three models were tested: an unadjusted model, a model adjusted for confounding variables (age, race, vision, number of diseases, physical performance, depressive symptoms), and a mediational model (benzodiazepine and psychotropic medication use, physical activity, emotional support). RESULTS: Nineteen percent of women reported two or more symptoms of anxiety at baseline. Unadjusted models indicate that anxiety was associated with a greater risk of worsening disability: activity of daily living (ADL) disability (relative risk (RR)=1.40, 95% confidence interval (CI)=1.10-1.79), mobility disability (RR=1.41, 95% CI=1.06-1.86), lifting disability (RR=1.54, 95% CI=1.20-1.97), and light housework disability (RR=1.77, 95% CI=1.32-2.37). After adjusting for confounding variables, anxiety continued to predict the development of two types of disability: ADL disability (RR=1.41, 95% CI=1.08-1.84) and light housework disability (RR=1.56, 95% CI=1.14-2.14). Finally, benzodiazepine and psychotropic medication use, physical activity, and emotional support were not significant mediators of the effect of anxiety on the development of a disability. CONCLUSION: Anxiety is a significant risk factor for the progression of disability in older women. Studies are needed to determine whether treatment of anxiety delays or prevents disabilit

Impact of leptin deficiency on male tibia and vertebral body 3D bone architecture independent of changes in body weight

Leptin an adipokine with potent effects on energy balance and body weight plays an important role in defining bone architecture in growing mammals. However, major changes in body weight can also influence morphology of trabecular and cortical bone. Therefore, we examined the impact of leptin deficiency on tibia and vertebral body 3D bone architecture independent of changes in body weight. Furthermore, advances in computational 3D image analysis suggest that average morphological values may mask regional specific differences in trabecular bone thickness. The study utilized leptin-deficient Ob/Ob mice (n = 8) weight-paired to C57BL/6 (C57) control mice (n = 8) which were split into either lean or obese groups for 24 ± 2 weeks. Whole tibias and L3 vertebrae were fixed before high resolution microcomputed tomography (μCT) scanning was performed. Leptin deficiency independent of body weight reduced tibia cortical bone volume, trabecular bone volume/tissue volume, number, and mineral density. Mean tibia trabecular thickness showed no significant differences between all groups; however, significant changes in trabecular thickness were found when analyzed by region. This study demonstrates that leptin deficiency significantly impacts tibia and vertebral body trabecular and cortical bone 3D architecture independent of changes in body weight